Publications by authors named "Kubera M"

178 Publications

Immune-Regulatory and Molecular Effects of Antidepressants on the Inflamed Human Keratinocyte HaCaT Cell Line.

Neurotox Res 2021 May 4. Epub 2021 May 4.

Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology Polish Academy of Sciences, Kraków, Poland.

Allergic contact dermatitis (ACD) is a T cell-mediated type of skin inflammation resulting from contact hypersensitivity (CHS) to antigens. There is strong comorbidity between ACD and major depression. Keratinocytes release immunomodulatory mediators including pro-inflammatory cytokines and chemokines, which modulate skin inflammation and are crucial cell type for the development of CHS. Our previous studies showed that fluoxetine and desipramine were effective in suppressing CHS in different mouse strains. However, the immune and molecular mechanisms underlying this effect remain to be explored. The aim of the current study was to determine the immune and molecular mechanisms of action of antidepressant drugs engaged in the inhibition of CHS response in the stimulated keratinocyte HaCaT cell line. The results show that LPS, TNF-α/IFN-γ, and DNFB stimulate HaCaT cells to produce large amounts of pro-inflammatory factors including IL-1β, IL-6, CCL2, and CXCL8. HaCaT stimulation was associated with increased expression of ICAM-1, a cell adhesion molecule, and decreased expression of E-cadherin. Imipramine, desipramine, and fluoxetine suppress the production of IL-1β, CCL2, as well as the expression of ICAM-1. LPS and TNF-α/IFN-γ activate p-38 kinase, but antidepressants do not regulate this pathway. LPS decreases E-cadherin protein expression and fluoxetine normalizes these effects. In summary, the antidepressant drugs examined in this study attenuate the stimulated secretion of pro-inflammatory cytokines, chemokines, and modulate adhesion molecule expression by the HaCaT cell line. Therefore, antidepressants may have some clinical efficacy in patients with ACD and patients with comorbid depression and contact allergy.
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http://dx.doi.org/10.1007/s12640-021-00367-5DOI Listing
May 2021

Increased Serum Immunoglobulin Responses to Gut Commensal Gram-Negative Bacteria in Unipolar Major Depression and Bipolar Disorder Type 1, Especially When Melancholia Is Present.

Neurotox Res 2020 Feb 4;37(2):338-348. Epub 2019 Dec 4.

Department of Psychiatry and Medical Psychology, Medical Faculty, Medical University of Plovdiv, Plovdiv, Bulgaria.

Major depressive disorder (MDD) is accompanied by higher serum IgM/IgA responses to LPS of Gram-negative bacteria, suggesting increased bacterial translocation and gut dysbiosis while the latter may occur in bipolar disorder (BD). There are differences between MDD and BD type 1 (BP1) and 2 (BP2) in nitro-oxidative stress biomarkers associated with leaky gut. This study examines serum IgM/IgA responses directed to LPS of 6 Gram-negative bacteria as well as IgG responses to oxidized LDL (oxLDL) in 29 BP1, 37 BP2, 44 MDD, and 30 healthy individuals. Increased IgM/IgA responses to Pseudomonas aeruginosa significantly discriminated patients with affective disorders (MDD plus BD) from controls. BP1 patients showed higher IgM responses to Morganella morganii as compared with MDD and BP2 patients. Patients with melancholia showed higher IgA responses to Citrobacter koseri as compared to controls and non-melancholic depression. The total score on the Hamilton Depression Rating Scale was significantly associated with IgA responses to C. koseri. IgG to oxLDL was significantly associated with increased bacterial translocation. In conclusion, MDD, BP1, and BP2 are accompanied by an immune response due to the increased load of LPS while these aberrations in the gut-brain axis are most pronounced in BP1 and melancholia. Activated oxidative stress pathways and autoimmune responses to oxidative specific epitopes in mood disorders may be driven by a breakdown in gut paracellular, transcellular, and/or vascular pathways. If replicated, drugs that protect the integrity of the gut barrier may offer novel therapeutic opportunities for BP1 and MDD.
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http://dx.doi.org/10.1007/s12640-019-00126-7DOI Listing
February 2020

The Role of Aberrations in the Immune-Inflammatory Response System (IRS) and the Compensatory Immune-Regulatory Reflex System (CIRS) in Different Phenotypes of Schizophrenia: the IRS-CIRS Theory of Schizophrenia.

Mol Neurobiol 2020 Feb 31;57(2):778-797. Epub 2019 Aug 31.

Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Several lines of evidence indicate that aberrations in immune-inflammatory pathways may contribute to the pathophysiology of schizophrenia spectrum disorders. Here, we propose a novel theoretical framework that was previously developed for major depression and bipolar disorder, namely, the compensatory immune-regulatory reflex system (CIRS), as applied to the neuro-immune pathophysiology of schizophrenia and its phenotypes, including first-episode psychosis (FEP), acute relapses, chronic and treatment-resistant schizophrenia (TRS), comorbid depression, and deficit schizophrenia. These schizophrenia phenotypes and manifestations are accompanied by increased production of positive acute-phase proteins, including haptoglobin and α2-macroglobulin, complement factors, and macrophagic M1 (IL-1β, IL-6, and TNF-α), T helper (Th)-1 (interferon-γ and IL-2R), Th-2 (IL-4, IL-5), Th-17 (IL-17), and T regulatory (Treg; IL-10 and transforming growth factor (TGF)-β1) cytokines, cytokine-induced activation of the tryptophan catabolite (TRYCAT) pathway, and chemokines, including CCL-11 (eotaxin), CCL-2, CCL-3, and CXCL-8. While the immune profiles in the different schizophrenia phenotypes indicate the activation of the immune-inflammatory response system (IRS), there are simultaneous signs of CIRS activation, including increased levels of the IL-1 receptor antagonist (sIL-1RA), sIL-2R and tumor necrosis factor-α receptors, Th-2 and Treg phenotypes with increased IL-4 and IL-10 production, and increased levels of TRYCATs and haptoglobin, α2-macroglobulin, and other acute-phase reactants, which have immune-regulatory and anti-inflammatory effects. Signs of activated IRS and CIRS pathways are also detected in TRS, chronic, and deficit schizophrenia, indicating that these conditions are accompanied by a new homeostatic setpoint between upregulated IRS and CIRS components. In FEP, increased baseline CIRS activity is a protective factor that may predict favorable clinical outcomes. Moreover, impairments in the CIRS are associated with deficit schizophrenia and greater impairments in semantic and episodic memory. It is concluded that CIRS plays a key role in the pathophysiology of schizophrenia by negatively regulating the primary IRS and contributing to recovery from the acute phase of illness. Therefore, components of the CIRS may offer promising therapeutic targets for schizophrenia.
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http://dx.doi.org/10.1007/s12035-019-01737-zDOI Listing
February 2020

Interaction of the immune-inflammatory and the kynurenine pathways in rats resistant to antidepressant treatment in model of depression.

Int Immunopharmacol 2019 Aug 5;73:527-538. Epub 2019 Jun 5.

Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smetna Street 12, PL 31-343 Krakow, Poland.

The kynurenine pathway (KP), a major route of tryptophan catabolism, may be associated with the pathophysiology of depressive disorders. KP is responsible for ca. 99% of brain tryptophan metabolism via its degradation to kynurenine (KYN) catalyzed by indoleamine 2,3-dioxygenase (IDO). Some cytokines, such as interferon-γ (IFN-γ) and interleukin (IL)-6 are potent inducers of IDO. KYN is further converted by kynurenine aminotransferase (KAT) to the more neuroprotective kynurenic acid or by kynurenine 3-monooxygenase (KMO) to neurotoxic 3-hydroxykynurenine. The aim of the present study was to delineate whether the administration of imipramine (IMI) to rats subjected to chronic mild stress (CMS) may reverse behavioral changes induced by CMS in association with changes in immune-inflammatory markers and KP. We confirmed that the CMS procedure modeled one of the main symptoms of depression, i.e. anhedonia, and administration of IMI for 5 weeks resulted in a significant reduction in anhedonia in a majority of animals (CMS IMI-R animals), whereas 20% of animals did not respond to IMI treatment (CMS IMI-NR animals). We established that CMS procedure increased IFN-γ and IDO mRNA and decreased KAT II mRNA expression in the rat cortex. In the cortex and hippocampus, IMI treatment and non-responsiveness to IMI (in CMS IMI-NR animals) were associated with increased IL-6 mRNA expression. In the spleen, CMS increased production of IFN-γ and IL-6 proteins, while these cytokines were decreased by IMI in CMS IMI-R animals. Chronic IMI administration to CMS rats decreased IDO and KMO mRNA and protein expression and increased KAT II/KMO mRNA and protein ratio in IMI responders (CMS IMI-R) in comparison to CMS rats. In CMS IMI-NR rats, a significant increase in IDO mRNA expression and protein level in comparison with IMI responders was observed. Our findings indicate that resistance to therapeutic action of IMI could be explained by a deficiency of the inhibitory properties of IMI on IDO, KMO and KYN synthesis in the cortex. We conclude that the antidepressant activity of IMI may, at least in part, be explained by modulatory activities on the KAT II/KMO ratio in brain areas.
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http://dx.doi.org/10.1016/j.intimp.2019.05.039DOI Listing
August 2019

Hypothalamic insulin and glucagon-like peptide-1 levels in an animal model of depression and their effect on corticotropin-releasing hormone promoter gene activity in a hypothalamic cell line.

Pharmacol Rep 2019 Apr 27;71(2):338-346. Epub 2018 Nov 27.

Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.

Background: In depression, excessive glucocorticoid action may cause maladaptive brain changes, including in the pathways controlling energy metabolism. Insulin and glucagon-like peptide-1 (GLP-1), besides regulation of glucose homeostasis, also possess neurotrophic properties. Current study was aimed at investigating the influence of prenatal stress (PS) on insulin, GLP-1 and their receptor (IR and GLP-1R) levels in the hypothalamus. GLP-1 and GLP-1R were assayed also in the hippocampus and frontal cortex - brain regions mainly affected in depression. The second objective was to determine the influence of exendin-4 and insulin on CRH promoter gene activity in in vitro conditions.

Methods: Adult male PS rats were subjected to acute stress and/or received orally glucose. Levels of hormones and their receptors were assayed with ELISA method. In vitro studies were performed on mHypoA-2/12 hypothalamic cell line, stably transfected with CRH promoter coupled with luciferase.

Results: PS has reduced GLP-1 and GLP-1R levels, attenuated glucose-induced increase in insulin concentration and increased the amount of phosphorylated IR in the hypothalamus of animals subjected to additional stress stimuli, and also decreased the GLP-1R level in the hippocampus. In vitro studies demonstrated that insulin is capable of increasing CRH promoter activity in the condition of stimulation of the cAMP/PKA pathway in the applied cellular model.

Conclusion: Prenatal stress may act as a preconditioning factor, affecting the concentrations of hormones such as insulin and GLP-1 in the hypothalamus in response to adverse stimuli. The decreased GLP-1R level in the hippocampus could be linked with the disturbances in neuronal plasticity.
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http://dx.doi.org/10.1016/j.pharep.2018.11.001DOI Listing
April 2019

Targeting the NLRP3 Inflammasome-Related Pathways via Tianeptine Treatment-Suppressed Microglia Polarization to the M1 Phenotype in Lipopolysaccharide-Stimulated Cultures.

Int J Mol Sci 2018 07 5;19(7). Epub 2018 Jul 5.

Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna St., 31-343 Krakow, Poland.

An increasing body of evidence postulates that microglia are the main mediators of inflammation-related disorders, including depression. Since activated microglia produce a wide range of pro- and anti-inflammatory factors, the modulation of M1/M2 microglial polarization by antidepressants may be crucial in the treatment of depression. The current paper aimed to investigate the impact of tianeptine on the microglia’s viability/death parameters, and on M1/M2 microglial activation in response to lipopolysaccharide (LPS) stimulation. Furthermore, the molecular mechanisms via which tianeptine affected the LPS-evoked changes were investigated. The results revealed that tianeptine had partially protective effects on the changes in microglia viability/death evoked by LPS. Tianeptine attenuated microglia activation by decreasing the expression of cluster of differentiation 40 (CD40), and major histocompatibility complex class II (MHC II) markers, as well as the release of pro-inflammatory factors: interleukin (IL)-1β, IL-18, IL-6, tumor necrosis factor alpha (TNF-α), and chemokine CC motif ligand 2 (CCL2), and the production of nitric oxide and reactive oxygen species. In contrast, we did not observe an impact of tianeptine on M2 microglia measured by IL-4, IL-10, TGF-β, and insulin-like growth factor 1 (IGF-1) expression. Moreover, we demonstrated an inhibitory effect of tianeptine on the LPS-induced activation of the nucleotide-binding oligomerization domain-like (NOD-like) receptor pyrin-containing 3 inflammasome (NLRP3) inflammasome subunits, NLRP3 and caspase-1, as well as the ability of tianeptine to reduce Toll-like receptor 4 (TLR4) levels, as well as the phosphorylation of extracellular signal-related kinases 1 and 2 (ERK1/2) and of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Collectively, we demonstrated that tianeptine has protective properties and inhibits M1 polarization, thus attenuating the production of inflammatory mediators. Moreover, we found that M1 microglia suppression may be related to the NLRP3 inflammasome and TLR4 signaling. These findings suggest that a better understanding of the multifaceted mechanisms of tianeptine action on microglia may increase the effectiveness of therapy, where inflammation is a central hallmark.
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http://dx.doi.org/10.3390/ijms19071965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073715PMC
July 2018

Targeting the NLRP3 Inflammasome-Related Pathways via Tianeptine Treatment-Suppressed Microglia Polarization to the M1 Phenotype in Lipopolysaccharide-Stimulated Cultures.

Int J Mol Sci 2018 07 5;19(7). Epub 2018 Jul 5.

Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna St., 31-343 Krakow, Poland.

An increasing body of evidence postulates that microglia are the main mediators of inflammation-related disorders, including depression. Since activated microglia produce a wide range of pro- and anti-inflammatory factors, the modulation of M1/M2 microglial polarization by antidepressants may be crucial in the treatment of depression. The current paper aimed to investigate the impact of tianeptine on the microglia’s viability/death parameters, and on M1/M2 microglial activation in response to lipopolysaccharide (LPS) stimulation. Furthermore, the molecular mechanisms via which tianeptine affected the LPS-evoked changes were investigated. The results revealed that tianeptine had partially protective effects on the changes in microglia viability/death evoked by LPS. Tianeptine attenuated microglia activation by decreasing the expression of cluster of differentiation 40 (CD40), and major histocompatibility complex class II (MHC II) markers, as well as the release of pro-inflammatory factors: interleukin (IL)-1β, IL-18, IL-6, tumor necrosis factor alpha (TNF-α), and chemokine CC motif ligand 2 (CCL2), and the production of nitric oxide and reactive oxygen species. In contrast, we did not observe an impact of tianeptine on M2 microglia measured by IL-4, IL-10, TGF-β, and insulin-like growth factor 1 (IGF-1) expression. Moreover, we demonstrated an inhibitory effect of tianeptine on the LPS-induced activation of the nucleotide-binding oligomerization domain-like (NOD-like) receptor pyrin-containing 3 inflammasome (NLRP3) inflammasome subunits, NLRP3 and caspase-1, as well as the ability of tianeptine to reduce Toll-like receptor 4 (TLR4) levels, as well as the phosphorylation of extracellular signal-related kinases 1 and 2 (ERK1/2) and of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Collectively, we demonstrated that tianeptine has protective properties and inhibits M1 polarization, thus attenuating the production of inflammatory mediators. Moreover, we found that M1 microglia suppression may be related to the NLRP3 inflammasome and TLR4 signaling. These findings suggest that a better understanding of the multifaceted mechanisms of tianeptine action on microglia may increase the effectiveness of therapy, where inflammation is a central hallmark.
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http://dx.doi.org/10.3390/ijms19071965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073715PMC
July 2018

Deficit schizophrenia is a discrete diagnostic category defined by neuro-immune and neurocognitive features: results of supervised machine learning.

Metab Brain Dis 2018 08 11;33(4):1053-1067. Epub 2018 Mar 11.

Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Deficit schizophrenia is characterized by neurocognitive impairments and changes in the patterning of IgA/IgM responses to plasma tryptophan catabolites (TRYCATs). In the current study, supervised pattern recognition methods, including logistic regression analysis (LRA), Support Vector Machine (SVM), and Soft Independent Modeling of Class Analogy (SIMCA), were used to examine whether deficit schizophrenia is a discrete diagnostic class with respect to Consortium To Establish a Registry for Alzheimer's disease (CERAD) and Cambridge Neuropsychological Test Automated Battery (CANTAB) tests and IgA/IgM responses to noxious (NOX) and generally more protective (PRO) TRYCATs. We recruited patients with (n = 40) and without (n = 40) deficit schizophrenia and healthy volunteers (n = 40). The combined use of TRYCAT and CERAD features strongly segregates deficit from nondeficit schizophrenia and healthy controls. Three out of the top five most important features in LRA, SVM and SIMCA agreed, namely two different NOX/PRO TRYCAT ratios and false memory recall. SIMCA shows that deficit schizophrenia is significantly separated from nondeficit schizophrenia and controls with as top 6 features IgA responses to picolinic acid, IgM responses to 3-OH-kynurenine and kynurenic acid, and impairments in Word List Memory and Verbal Fluency Tests and Mini-Mental State Examination. Nevertheless, nondeficit schizophrenia was not significantly separated from controls. The results show that schizophrenia is not a unitary disease with mere continuous differences in severity of illness between apparent subtypes. Deficit schizophrenia is a qualitatively distinct class defined by neuroimmune (autoimmune responses to TRYCATs) and neurocognitive (episodic and semantic memory) features coupled or not with clinical (negative) symptoms.
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http://dx.doi.org/10.1007/s11011-018-0208-4DOI Listing
August 2018

Regulators of glucocorticoid receptor function in an animal model of depression and obesity.

J Neuroendocrinol 2018 Mar 9. Epub 2018 Mar 9.

Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, 31-343, Kraków, Smętna 12,, Poland.

Obesity is a disease that often co-occurs with depression, and some evidence indicates that chronic stress in the perinatal period, in association with overactive glucocorticoids, can cause permanent changes that increase the risk of the development of both depression and obesity later in life. However, the mechanism responsible for the overly potent action of glucocorticoids in both depression and obesity is not known. The aim of the present study was to determine the expression of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) and the factors that affect GR function (FKBP51, Bag-1 and HSP70) in a prenatal stress animal model of depression, a model of obesity and a model of both depression and obesity. Prenatal stress but not high-fat diet (HFD) was found to decrease the GR concentration in the frontal cortex. The level of the Bag-1M (46 kDa) isoform was also decreased in this structure but only in prenatal-stressed animals that did not show depression-like behaviour in the Porsolt test and were fed the standard diet (STD). In the model of depression employed here, decreases in MR expression and GR co-chaperone (FKBP51) levels in the hippocampus were also observed, and HFD intensified the prenatal stress-induced changes in MR expression. The obtained results indicated that prenatal stress affected the expression of GRs, MRs and their co-chaperones in the brain, but its effects were different in the frontal cortex and hippocampus. The decrease in MR density in the hippocampus and increased plasma insulin level seemed to be the most significant changes observed in the model of the co-occurrence of depression and obesity, which could limit the neuroprotective effects associated with the activation of MR and be a marker of peripheral insulin resistance, respectively. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/jne.12591DOI Listing
March 2018

The Modulatory Properties of Chronic Antidepressant Drugs Treatment on the Brain Chemokine - Chemokine Receptor Network: A Molecular Study in an Animal Model of Depression.

Front Pharmacol 2017 1;8:779. Epub 2017 Nov 1.

Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.

An increasing number of studies indicate that the chemokine system may be the third major communication system of the brain. Therefore, the role of the chemokine system in the development of brain disorders, including depression, has been recently proposed. However, little is known about the impact of the administration of various antidepressant drugs on the brain chemokine - chemokine receptor axis. In the present study, we used an animal model of depression based on the prenatal stress procedure. We determined whether chronic treatment with tianeptine, venlafaxine, or fluoxetine influenced the evoked by prenatal stress procedure changes in the mRNA and protein levels of the homeostatic chemokines, CXCL12 (SDF-1α), CX3CL1 (fractalkine) and their receptors, in the hippocampus and frontal cortex. Moreover, the impact of mentioned antidepressants on the TGF-β, a molecular pathway related to fractalkine receptor (CX3CR1), was explored. We found that prenatal stress caused anxiety and depressive-like disturbances in adult offspring rats, which were normalized by chronic antidepressant treatment. Furthermore, we showed the stress-evoked CXCL12 upregulation while CXCR4 downregulation in hippocampus and frontal cortex. CXCR7 expression was enhanced in frontal cortex but not hippocampus. Furthermore, the levels of CX3CL1 and CX3CR1 were diminished by prenatal stress in the both examined brain areas. The mentioned changes were normalized with various potency by chronic administration of tested antidepressants. All drugs in hippocampus, while tianeptine and venlafaxine in frontal cortex normalized the CXCL12 level in prenatally stressed offspring. Moreover, in hippocampus only fluoxetine enhanced CXCR4 level, while fluoxetine and tianeptine diminished CXCR7 level in frontal cortex. Additionally, the diminished by prenatal stress levels of CX3CL1 and CX3CR1 in the both examined brain areas were normalized by chronic tianeptine and partially fluoxetine administration. Tianeptine modulate also brain TGF-β signaling in the prenatal stress-induced animal model of depression. Our results provide new evidence that not only prenatal stress-induced behavioral disturbances but also changes of CXCL12 and their receptor and at less extend in CX3CL1-CX3CR1 expression may be normalized by chronic antidepressant drug treatment. In particular, the effect on the CXCL12 and their CXCR4 and CXCR7 receptors requires additional studies to elucidate the possible biological consequences.
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http://dx.doi.org/10.3389/fphar.2017.00779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5671972PMC
November 2017

The effects of pessimism on cell-mediated immunity in rats.

Prog Neuropsychopharmacol Biol Psychiatry 2018 Jan 6;80(Pt C):295-303. Epub 2017 Jun 6.

Institute of Pharmacology, Polish Academy of Sciences, Affective Cognitive Neuroscience Lab, Department of Behavioral Neuroscience and Drug Development, 12 Smetna Street, 31-343 Krakow, Poland.

We used a recently developed ambiguous-cue interpretation (ACI) paradigm to investigate whether 'optimism' and 'pessimism' as behavioural traits may be interrelated with immune functions in rodents. To this aim, in a series of ACI tests (cognitive bias screening, CBS), we identified rats that displayed 'pessimistic' and 'optimistic' traits. We found significant differences in immune biomarkers between 'optimistic' and 'pessimistic' animals. Moreover 'pessimism' was associated with significantly lower relative weight of the spleen and thymus, significantly decreased proliferative activity of splenocytes. Pessimism was associated with an increased production of interleukin-(IL)1β and IL-4, activin A, l-selectin, interferon (IFN)-γ and some chemokines and receptors for advanced glycation endproducts. The findings indicate an inflammatory profile in "pessimistic" animals.
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http://dx.doi.org/10.1016/j.pnpbp.2017.04.034DOI Listing
January 2018

Suppression of pro-inflammatory cytokine expression and lack of anti-depressant-like effect of fluoxetine in lipopolysaccharide-treated old female mice.

Int Immunopharmacol 2017 Jul 3;48:35-42. Epub 2017 May 3.

Department of Brain Biochemistry, Institute of Pharmacology, Polish Academy of Sciences, Smetna Street 12, PL 31-343 Krakow, Poland.

Some antidepressants show a significantly lower efficacy in elderly patients, particularly in women. Previous studies have shown that antidepressants administered to young animals reduced depression-like symptoms induced by lipopolysaccharide (LPS). The aim of this study was to find out whether the antidepressant and anti-inflammatory properties of fluoxetine (FLU) can be observed also in old female C57BL/6J mice. A depression-like state was evoked by the administration of LPS (100μg/kg for 4 consecutive days) which was followed by reduction of sucrose preference (anhedonia) and enhancement of immobility-time in the forced swim test (FST). Animals, which received FLU (10mg/kg, 11days) exhibited a decreased LPS-induced expression of some inflammatory cytokines in the hippocampus and spleen but this effect was not accompanied by beneficial changes in animals' behavior. Despite the lack of antidepressant-properties of FLU in this model, our studies have proven significant profound anti-inflammatory properties of chronic FLU treatment which may suggest its suitability for fending off inflammatory processes in the elderly.
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http://dx.doi.org/10.1016/j.intimp.2017.04.021DOI Listing
July 2017

Erratum to "Inhibition of 2,4-dinitrofluorobenzene-induced contact hypersensitivity reaction by antidepressant drugs".

Pharmacol Rep 2017 05;69(3):583

Maes Clinics & TRIA, 998 Rimklongsamsen Road, Bangkok, 10310, Thailand.

The authors wish to note an incorrectly listed financial support grant. The National Science Centre grant 2011/01/B/NZ6/00300 was inadvertently listed. The authors regret this error. The correct Acknowledgements read as follows.
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http://dx.doi.org/10.1016/j.pharep.2017.01.013DOI Listing
May 2017

Stimulatory effect of desipramine on lung metastases of adenocarcinoma MADB 106 in stress highly-sensitive and stress non-reactive rats.

Prog Neuropsychopharmacol Biol Psychiatry 2018 Jan 20;80(Pt C):279-290. Epub 2017 Apr 20.

Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, PL 31-343 Krakow, Poland.

The effect of antidepressant drugs on tumor progress is very poorly recognized. The aim of the present study was to examine the effect of individual reactivity to stress and 24-day desipramine (DES) administration on the metastatic colonization of adenocarcinoma MADB 106 cells in the lungs of Wistar rats. Wistar rats were subjected to stress procedure according to the chronic mild stress (CMS) model of depression for two weeks and stress highly-sensitive (SHS) and stress non-reactive (SNR) rats were selected. SHS rats were more prone to cancer metastasis than SNR ones and chronic DES treatment further increased the number of lung metastases by 59% and 50% in comparison to vehicle-treated appropriate control rats. The increase in lung metastases was connected with DES-induced skew macrophage activity towards M2 functional phenotype in SHS and SNR rats. Moreover, during 24h after DES injection in healthy rats, the decreased number of TCD8 and B cells in SHS and SNR rats as well as NK cell cytotoxic activity in SNR rats could be attributed to the lowered capacity to defend against cancer metastasis observed in chronic DES treated and tumor injected rats.
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http://dx.doi.org/10.1016/j.pnpbp.2017.04.024DOI Listing
January 2018

Depression in cancer: The many biobehavioral pathways driving tumor progression.

Cancer Treat Rev 2017 Jan 16;52:58-70. Epub 2016 Nov 16.

Department of Clinical Medicine and Translational Psychiatry Research Group, Faculty of Medicine, Fortaleza, CE, Brazil. Electronic address:

Major Depressive Disorder (MDD) is common among cancer patients, with prevalence rates up to four-times higher than the general population. Depression confers worse outcomes, including non-adherence to treatment and increased mortality in the oncology setting. Advances in the understanding of neurobiological underpinnings of depression have revealed shared biobehavioral mechanisms may contribute to cancer progression. Moreover, psychosocial stressors in cancer promote: (1) inflammation and oxidative/nitrosative stress; (2) a decreased immunosurveillance; and (3) a dysfunctional activation of the autonomic nervous system and of the hypothalamic-pituitaryadrenal axis. Consequently, the prompt recognition of depression among patients with cancer who may benefit of treatment strategies targeting depressive symptoms, cognitive dysfunction, fatigue and sleep disturbances, is a public health priority. Moreover, behavioral strategies aiming at reducing psychological distress and depressive symptoms, including addressing unhealthy diet and life-style choices, as well as physical inactivity and sleep dysfunction, may represent important strategies not only to treat depression, but also to improve wider cancer-related outcomes. Herein, we provide a comprehensive review of the intertwined biobehavioral pathways linking depression to cancer progression. In addition, the clinical implications of these findings are critically reviewed.
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http://dx.doi.org/10.1016/j.ctrv.2016.11.004DOI Listing
January 2017

Beneficial impact of intracerebroventricular fractalkine administration on behavioral and biochemical changes induced by prenatal stress in adult rats: Possible role of NLRP3 inflammasome pathway.

Biochem Pharmacol 2016 08 17;113:45-56. Epub 2016 May 17.

Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Krakow, Poland. Electronic address:

Several lines of evidence indicate that adverse experience in early life may be a triggering factor for pathological inflammatory processes and lead to the development of depression. Fractalkine (CX3CL1), a chemokine, plays an important role not only in the migration, differentiation and proliferation of neuronal and glial cells but also in the regulation of neuronal-microglial signaling and the production of pro-inflammatory factors. In the present study, we examined the impact of a prenatal stress procedure on the expression of fractalkine in the hippocampus and frontal cortex of young and adult male rats. Furthermore, we measured the age-dependent effect of stress during pregnancy on the expression of pro-inflammatory factors IL-1β, IL-18, TNF-α, IL-6, and CCL2 in both brain structures. Next, to illustrate the link between fractalkine signaling and the behavioral and biochemical changes induced by prenatal stress, adult prenatally stressed offspring were injected intracerebroventricularly (icv) with exogenous fractalkine. We reported that prenatal stress leads to long-lasting deficits in fractalkine signaling and enhanced inflammatory activation. The study demonstrates that icv administration of fractalkine attenuates the behavioural changes evoked by prenatal stress procedure in adult animals. Moreover, fractalkine administration, exhibits anti-inflammatory action, mainly in the frontal cortex of adult prenatally stressed rats. The effect of fractalkine is related to inhibition of NLRP3 inflammasome. However, its action on the other members of NOD-like receptor family (NLR) cannot be excluded. These findings provide new in vivo evidence that the behavioral and inflammatory disturbances observed in adult prenatally stressed rats may be related to long-lasting malfunctions in fractalkine signaling.
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http://dx.doi.org/10.1016/j.bcp.2016.05.008DOI Listing
August 2016

The Effect of Chronic Mild Stress and Imipramine on the Markers of Oxidative Stress and Antioxidant System in Rat Liver.

Neurotox Res 2016 08 10;30(2):173-84. Epub 2016 Mar 10.

Department of Neurochemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343, Kraków, Poland.

Liver abnormalities have been reported to occur in up to 20 % of patients on a long-term therapy with the tricyclic antidepressant drug imipramine (IMI). The mechanism involved in this IMI-induced process is unknown but a contribution of oxidative stress is highly likely. Chronic mild stress (CMS) is widely used for modeling depressive-like behavior in rats. In the present study, we examined the effects of CMS and chronic IMI treatment, applied alone or in combination, on the levels of oxidative stress markers, such as reactive oxygen species (ROS), malondialdehyde (MDA), non-protein sulfhydryl groups, and sulfane sulfur as well as on activities of key antioxidant enzymes: catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase in the rat liver. Administration of IMI for 5 weeks to rats subjected to CMS resulted in a gradual significant reduction of anhedonia measured by sucrose intake, in a majority of animals (CMS IMI-reactive, CMS IMI-R), although about 20 % of rats did not respond to the IMI treatment (CMS IMI non-reactive, CMS IMI-NR). CMS-induced hepatic oxidative stress, estimated by increased ROS and MDA concentrations, was not prevented by the IMI administration, moreover, in CMS IMI-NR animals, the level of the marker of lipid peroxidation, i.e., MDA was increased in comparison to CMS-subjected rats and activity of antioxidant enzymes (GPx and CAT) was decreased compared to IMI-treated rats. The clinical significance of this observation remains to be established.
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http://dx.doi.org/10.1007/s12640-016-9614-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947122PMC
August 2016

The effect of chronic tianeptine administration on the brain mitochondria: direct links with an animal model of depression.

Mol Neurobiol 2016 12 2;53(10):7351-7362. Epub 2016 Mar 2.

Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St, 31-343, Kraków, Poland.

A growing body of evidence has focused on the impact of mitochondrial disturbances in the development of depression, but little data exist regarding the effects of chronic administration of antidepressant drugs on the brain's mitochondrial protein profile. The aim of this study was to investigate the impact of chronic treatment with an atypical antidepressant drug-tianeptine-on the mitochondria-enriched subproteome profile in the hippocampus and the frontal cortex of 3-month-old male rats following a prenatal stress procedure. Rats that were exposed to a prenatal stress procedure displayed depressive- and anxiety-like disturbances based on the elevated plus-maze and Porsolt tests. Moreover, two-dimensional electrophoresis coupled with mass spectrometry showed structure-dependent mitoproteome changes in brains of prenatally stressed rats after chronic tianeptine administration. A component of 2-oxoglutarate and succinate flavoprotein subunit dehydrogenases, isocitrate subunit alpha, was upregulated in the hippocampus. In the frontal cortex, there was a striking increase in the expression of glutamate dehydrogenase and cytochrome bc1 complex subunit 2. These findings suggest that mitochondria are underappreciated targets for therapeutic interventions, and mitochondrial function may be crucial for the effective treatment of stress-related diseases.
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http://dx.doi.org/10.1007/s12035-016-9807-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104776PMC
December 2016

Chronic mild stress influences nerve growth factor through a matrix metalloproteinase-dependent mechanism.

Psychoneuroendocrinology 2016 Apr 24;66:11-21. Epub 2015 Dec 24.

Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland. Electronic address:

Stress is generally a beneficial experience that motivates an organism to action to overcome the stressful challenge. In particular situations, when stress becomes chronic might be harmful and devastating. The hypothalamus is a critical coordinator of stress and the metabolic response; therefore, disruptions in this structure may be a significant cause of the hormonal and metabolic disturbances observed in depression. Chronic stress induces adverse changes in the morphology of neural cells that are often associated with a deficiency of neurotrophic factors (NTFs); additionally, many studies indicate that insufficient NTF synthesis may participate in the pathogenesis of depression. The aim of the present study was to determine the expression of the nerve growth factor (NGF) in the hypothalamus of male rats subjected to chronic mild stress (CMS) or to prenatal stress (PS) and to PS in combination with an acute stress event (AS). It has been found that chronic mild stress, but not prenatal stress, acute stress or a combination of PS with AS, decreased the concentration of the mature form of NGF (m-NGF) in the rat hypothalamus. A discrepancy between an increase in the Ngf mRNA and a decrease in the m-NGF levels suggested that chronic mild stress inhibited NGF maturation or enhanced the degradation of this factor. We have shown that NGF degradation in the hypothalamus of rats subjected to chronic mild stress is matrix metalloproteinase-dependent and related to an increase in the active forms of some metalloproteinases (MMP), including MMP2, MMP3, MMP9 and MMP13, while the NGF maturation process does not seem to be changed. We suggested that activated MMP2 and MMP9 potently cleave the mature but not the pro- form of NGF into biologically inactive products, which is the reason for m-NGF decomposition. In turn, the enhanced expression of Ngf in the hypothalamus of these rats is an attempt to overcome the reduced levels of m-NGF. Additionally, the decreased level of m-NGF together with the increased level of pro-NGF can decrease TrkA-mediated neuronal survival signalling and enhance the action of pro-NGF on the p75(NTR) receptor, respectively, to evoke pro-apoptotic signalling. This hypothesis is supported by elevated levels of the caspase-3 mRNA in the hypothalamus of rats subjected to chronic mild stress.
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http://dx.doi.org/10.1016/j.psyneuen.2015.12.019DOI Listing
April 2016

Increased expression of activation antigens on CD8+ T lymphocytes in Myalgic Encephalomyelitis/chronic fatigue syndrome: inverse associations with lowered CD19+ expression and CD4+/CD8+ ratio, but no associations with (auto)immune, leaky gut, oxidative and nitrosative stress biomarkers.

Neuro Endocrinol Lett 2015 ;36(5):439-46

Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.

Background: There is now evidence that specific subgroups of patients with Myalgic Encephalomyelitis / chronic fatigue syndrome (ME/CFS) suffer from a neuro-psychiatric-immune disorder. This study was carried out to delineate the expression of the activation markers CD38 and human leukocyte antigen (HLA) DR on CD4+ and CD8+ peripheral blood lymphocytes in ME/CFS.

Methods: Proportions and absolute numbers of peripheral lymphocytes expressing CD3+, CD19+, CD4+, CD8+, CD38+ and HLA-DR+ were measured in ME/CFS (n=139), chronic fatigue (CF, n=65) and normal controls (n=40).

Results: The proportions of CD3+, CD8+, CD8+CD38+ and CD8+HLA-DR+ were significantly higher in ME/CFS patients than controls, while CD38+, CD8+CD38+, CD8+HLA-DR+ and CD38+HLA-DR+ were significantly higher in ME/CFS than CF. The percentage of CD19+ cells and the CD4+/CD8+ ratio were significantly lower in ME/CFS and CF than in controls. There were highly significant inverse correlations between the increased expression of CD38+, especially that of CD8+CD38+, and the lowered CD4+/CD8+ ratio and CD19+ expression. There were no significant associations between the flow cytometric results and severity or duration of illness and peripheral blood biomarkers of oxidative and nitrosative stress (O&NS, i.e. IgM responses to O&N modified epitopes), leaky gut (IgM or IgA responses to LPS of gut commensal bacteria), cytokines (interleukin-1, tumor necrosis factor-α), neopterin, lysozyme and autoimmune responses to serotonin.

Conclusions: The results support that a) increased CD38 and HLA-DR expression on CD8+ T cells are biomarkers of ME/CFS; b) increased CD38 antigen expression may contribute to suppression of the CD4+/CD8+ ratio and CD19+ expression; c) there are different immune subgroups of ME/CFS patients, e.g. increased CD8+ activation marker expression versus inflammation or O&NS processes; and d) viral infections or reactivation may play a role in a some ME/CFS patients.
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April 2016

Anti-inflammatory properties of tianeptine on lipopolysaccharide-induced changes in microglial cells involve toll-like receptor-related pathways.

J Neurochem 2016 Mar;136(5):958-70

Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.

Accumulating evidence suggests that activation of microglia plays a key role in the pathogenesis of depression. Activated microglia produce a wide range of factors whose prolonged or excessive release may lead to brain disorders. Thus, the inhibition of microglial cells may be beneficial in the treatment of depressive diseases. Tianeptine is an atypical antidepressant drug with proven clinical efficacy, but its mechanism of action remains still not fully understood. In the present study, using microglial cultures we investigated whether tianeptine modifies microglial activation after lipopolysaccharide (LPS) stimulation and which intracellular pathways are involved in the activity of this antidepressant. Our study shows that tianeptine attenuated the LPS-evoked inflammatory activation of microglia by decreasing the expression of proinflammatory cytokines such as IL-1β, IL-18, IL-6 and tumor necrosis factor α (TNF-α), the release of nitric oxide (NO) and reactive oxygen species (ROS) as well as the expression of inducible nitric oxide synthase. Analyses of signaling pathways demonstrate that tianeptine led to the suppression of LPS-induced TLR4 expression and ERK1/2 phosphorylation. Furthermore, our study reveals the inhibitory impact of tianeptine on caspase-3-induced PKCδ degradation and consequently on the activation of NF-κB factor in microglial cells. Taken together, present results show anti-inflammatory properties of tianeptine in microglial cultures stimulated by LPS. This study provides evidence that the inhibition of microglial activation may underlie the therapeutic activity of tianeptine. Our findings show the anti-inflammatory effect of tianeptine (TIA) in lipopolisaccharide (LPS)-stimulated microglial cells. The beneficial tianeptine action is mediated through the inhibition of Toll-like receptor 4 (TLR4) expression as well as the TLR4-related pathways: extracellular signal-regulated kinase 1/2 (ERK1/2), caspase-3-dependent protein kinase δ (PKCδ) cleavage and the expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). These findings may provide a new therapeutic strategy for treatment of disorders based on neuroinflammation, including depression.
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http://dx.doi.org/10.1111/jnc.13452DOI Listing
March 2016

The Beneficial Impact of Antidepressant Drugs on Prenatal Stress-Evoked Malfunction of the Insulin-Like Growth Factor-1 (IGF-1) Protein Family in the Olfactory Bulbs of Adult Rats.

Neurotox Res 2016 Feb 26;29(2):288-98. Epub 2015 Nov 26.

Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St, 31-343, Cracow, Poland.

Insulin-like growth factor-1 (IGF-1) promotes the growth, differentiation, and survival of both neurons and glial cells, and it is believed to exert antidepressant-like activity. Thus, disturbances in the IGF-1 system could be responsible for the course of depression. To date, there have been no papers showing the impact of chronic antidepressant treatment on the IGF-1 network in the olfactory bulb (OB) in an animal model of depression. Prenatal stress was used as model of depression. Twenty-four 3-month-old male offspring of control and stressed mothers were subjected to behavioral testing (forced swim test). The mRNA expression of IGF-1 and IGF-1 receptor (IGF-1R) and the protein level of IGF-1 and its phosphorylation, as well as the concentrations of IGF-binding proteins (IGFBP-2, -4, -3, and -6), were measured in OBs before and after chronic imipramine, fluoxetine, or tianeptine administration. Adult rats exposed prenatally to stressful stimuli displayed not only depression-like behavior but also decreased IGF-1 expression, dysregulation in the IGFBP network, and diminished mRNA expression, as well as IGF-1R phosphorylation, in the OB. The administration of antidepressants normalized most of the changes in the IGF-1 system of the OB evoked by prenatal stress. These results suggested a beneficial effect of chronic antidepressant drug treatment in the alleviation of IGF-1 family malfunction in OBs in an animal model of depression.
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http://dx.doi.org/10.1007/s12640-015-9575-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712215PMC
February 2016

Inhibitory effect of antidepressant drugs on contact hypersensitivity reaction is connected with their suppressive effect on NKT and CD8(+) T cells but not on TCR delta T cells.

Int Immunopharmacol 2015 Oct 24;28(2):1091-6. Epub 2015 Aug 24.

Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland.

Background: Contact hypersensitivity (CHS) reaction induced by a topical application of hapten is a cell-mediated antigen-specific type of skin inflammation mediated by interaction of several subtypes of T cell subpopulations. Recently, it has been shown that antidepressant drugs inhibit CHS reaction, although the mechanism of this effect remains unknown. The aim of the present study was to investigate the effect of 2-week desipramine or fluoxetine administration on the CHS reaction induced by picryl chloride (PCL) application in B10.PL mice and in knock-out mice established on B10.PL background: TCRδ(-/-) mice lacking TCRγδ T lymphocytes; β2m(-/-) mice lacking CD8(+) T lymphocytes and CD1d(-/-) mice lacking CD1d dependent natural killer T (NKT) lymphocytes.

Methods: B10.PL, TCRδ(-/-), β2m(-/-) and CD1d(-/-) mice were divided into six groups: 1) vehicle-treated negative control group; 2) desipramine-treated negative control group; 3) fluoxetine-treated negative control group; 4) vehicle and PCL-treated group (positive control group); 5) desipramine and PCL-treated group; and 6) fluoxetine and PCL-treated group. CHS to PCL was tested by evaluation of ear swelling. Metabolic activity of spleen and lymph node cells were estimated by MTT test.

Results: The antidepressants significantly suppressed the CHS reaction in B10.PL mice: desipramine by 55% and fluoxetine by 42% compared to the positive control. This effect was even stronger in TCRδ(-/-) mice, in which fluoxetine reduced the ear swelling by 73% in comparison with the vehicle-treated positive control group. On the other hand, desipramine and fluoxetine did not inhibit CHS reaction in β2m(-/-) and CD1d(-/-) mice. Moreover, PCL increased metabolic and/or proliferative activity of splenocytes in all four strains of mice whereas the antidepressants decreased this activity of splenocytes in B10.PL, TCRδ(-/-) and CD1d(-/-) mice.

Conclusion: The results of the present study show that lack of CD8(+) T cells or NKT cells abolishes the immunosuppressive effect of antidepressant drugs on PCL-induced CHS reaction in mice. These results suggest that antidepressant drug-induced inhibition of CHS reaction is connected with their inhibitory effect on ability of CD8(+) T cells and NKT cells to induce and/or escalate CHS reaction. TCRγδ cells seem not to be involved in antidepressant-induced suppression of CHS.
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http://dx.doi.org/10.1016/j.intimp.2015.08.001DOI Listing
October 2015

Maternal stress predicts altered biogenesis and the profile of mitochondrial proteins in the frontal cortex and hippocampus of adult offspring rats.

Psychoneuroendocrinology 2015 Oct 28;60:151-62. Epub 2015 Jun 28.

Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Krakow, Poland. Electronic address:

Currently, much attention is focused on the influence of mitochondrial disturbances at the onset of depression. The goal of this study was to investigate the impact of prenatal stress (an animal model of depression) on the mitochondrial biogenesis proteins and mitoproteome profile in the frontal cortex and hippocampus of adult 3-month-old male rats following a prenatal stress procedure. Our results show that rats that were exposed to prenatal stress stimuli displayed depression-like behaviors based on the sucrose preference and elevated plus maze tests. It has been found that the level of the PGC-1α protein was reduced in the frontal cortex and hippocampus of the adult offspring after the prenatal stress procedure. Moreover, in the frontal cortex, the level of the pro-apoptotic protein Bax was up-regulated. Two-dimensional electrophoresis coupled with mass spectrometry showed the statistically significant down-regulation of the mitochondrial ribosomal protein L12 (Mrpl12) and mitochondrial NADH dehydrogenase [ubiquinone] flavoprotein 2 (NDUFV2) as well as the up-regulation of the Tubulin Polymerization Promoting Proteins (Tppp/p25) in the frontal cortex. In contrast, in the hippocampus, the mitochondrial pyruvate dehydrogenase E1 component subunit beta, the voltage-dependent anion-selective channel protein 2 (VDAC2), and the GTP-binding nuclear protein RAN (RAN) were down-regulated and the expression of phosphatidylethanolamine-binding protein 1 (PEBP-1) was enhanced. These findings provide new evidence that stress during pregnancy may lead not only to behavioral deficits, but also to disturbances in the brain mitoproteome profile in adult rat offspring.
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http://dx.doi.org/10.1016/j.psyneuen.2015.06.015DOI Listing
October 2015

Toward Omics-Based, Systems Biomedicine, and Path and Drug Discovery Methodologies for Depression-Inflammation Research.

Mol Neurobiol 2016 07 2;53(5):2927-2935. Epub 2015 May 2.

IMPACT Research Center, Deakin University, Geelong, Australia.

Meta-analyses confirm that depression is accompanied by signs of inflammation including increased levels of acute phase proteins, e.g., C-reactive protein, and pro-inflammatory cytokines, e.g., interleukin-6. Supporting the translational significance of this, a meta-analysis showed that anti-inflammatory drugs may have antidepressant effects. Here, we argue that inflammation and depression research needs to get onto a new track. Firstly, the choice of inflammatory biomarkers in depression research was often too selective and did not consider the broader pathways. Secondly, although mild inflammatory responses are present in depression, other immune-related pathways cannot be disregarded as new drug targets, e.g., activation of cell-mediated immunity, oxidative and nitrosative stress (O&NS) pathways, autoimmune responses, bacterial translocation, and activation of the toll-like receptor and neuroprogressive pathways. Thirdly, anti-inflammatory treatments are sometimes used without full understanding of their effects on the broader pathways underpinning depression. Since many of the activated immune-inflammatory pathways in depression actually confer protection against an overzealous inflammatory response, targeting these pathways may result in unpredictable and unwanted results. Furthermore, this paper discusses the required improvements in research strategy, i.e., path and drug discovery processes, omics-based techniques, and systems biomedicine methodologies. Firstly, novel methods should be employed to examine the intracellular networks that control and modulate the immune, O&NS and neuroprogressive pathways using omics-based assays, including genomics, transcriptomics, proteomics, metabolomics, epigenomics, immunoproteomics and metagenomics. Secondly, systems biomedicine analyses are essential to unravel the complex interactions between these cellular networks, pathways, and the multifactorial trigger factors and to delineate new drug targets in the cellular networks or pathways. Drug discovery processes should delineate new drugs targeting the intracellular networks and immune-related pathways.
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http://dx.doi.org/10.1007/s12035-015-9183-5DOI Listing
July 2016

Brain glucose metabolism in an animal model of depression.

Neuroscience 2015 Jun 25;295:198-208. Epub 2015 Mar 25.

Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland. Electronic address:

An increasing number of data support the involvement of disturbances in glucose metabolism in the pathogenesis of depression. We previously reported that glucose and glycogen concentrations in brain structures important for depression are higher in a prenatal stress model of depression when compared with control animals. A marked rise in the concentrations of these carbohydrates and glucose transporters were evident in prenatally stressed animals subjected to acute stress and glucose loading in adulthood. To determine whether elevated levels of brain glucose are associated with a change in its metabolism in this model, we assessed key glycolytic enzymes (hexokinase, phosphofructokinase and pyruvate kinase), products of glycolysis, i.e., pyruvate and lactate, and two selected enzymes of the tricarboxylic acid cycle (pyruvate dehydrogenase and α-ketoglutarate dehydrogenase) in the hippocampus and frontal cortex. Additionally, we assessed glucose-6-phosphate dehydrogenase activity, a key enzyme in the pentose phosphate pathway (PPP). Prenatal stress increased the levels of phosphofructokinase, an important glycolytic enzyme, in the hippocampus and frontal cortex. However, prenatal stress had no effect on hexokinase or pyruvate kinase levels. The lactate concentration was elevated in prenatally stressed rats in the frontal cortex, and pyruvate levels remained unchanged. Among the tricarboxylic acid cycle enzymes, prenatal stress decreased the level of pyruvate dehydrogenase in the hippocampus, but it had no effect on α-ketoglutarate dehydrogenase. Like in the case of glucose and its transporters, also in the present study, differences in markers of glucose metabolism between control animals and those subjected to prenatal stress were not observed under basal conditions but in rats subjected to acute stress and glucose load in adulthood. Glucose-6-phosphate dehydrogenase activity was not reduced by prenatal stress but was found to be even higher in animals exposed to all experimental conditions, i.e., prenatal stress, acute stress, and glucose administration. Our data indicate that glycolysis is increased and the Krebs cycle is decreased in the brain of a prenatal stress animal model of depression.
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http://dx.doi.org/10.1016/j.neuroscience.2015.03.046DOI Listing
June 2015

Prenatal stress is a vulnerability factor for altered morphology and biological activity of microglia cells.

Front Cell Neurosci 2015 12;9:82. Epub 2015 Mar 12.

Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences Kraków, Poland.

Several lines of evidence suggest that the dysregulation of the immune system is an important factor in the development of depression. Microglia are the resident macrophages of the central nervous system and a key player in innate immunity of the brain. We hypothesized that prenatal stress (an animal model of depression) as a priming factor could affect microglial cells and might lead to depressive-like disturbances in adult male rat offspring. We investigated the behavioral changes (sucrose preference test, Porsolt test), the expression of C1q and CD40 mRNA and the level of microglia (Iba1 positive) in 3-month-old control and prenatally stressed male offspring rats. In addition, we characterized the morphological and biochemical parameters of potentially harmful (NO, iNOS, IL-1β, IL-18, IL-6, TNF-α, CCL2, CXCL12, CCR2, CXCR4) and beneficial (insulin-like growth factor-1 (IGF-1), brain derived neurotrophic factor (BDNF)) phenotypes in cultures of microglia obtained from the cortices of 1-2 days old control and prenatally stressed pups. The adult prenatally stressed rats showed behavioral (anhedonic- and depression-like) disturbances, enhanced expression of microglial activation markers and an increased number of Iba1-immunopositive cells in the hippocampus and frontal cortex. The morphology of glia was altered in cultures from prenatally stressed rats, as demonstrated by immunofluorescence microscopy. Moreover, in these cultures, we observed enhanced expression of CD40 and MHC II and release of pro-inflammatory cytokines, including IL-1β, IL-18, TNF-α and IL-6. Prenatal stress significantly up-regulated levels of the chemokines CCL2, CXCL12 and altered expression of their receptors, CCR2 and CXCR4 while IGF-1 production was suppressed in cultures of microglia from prenatally stressed rats. Our results suggest that prenatal stress may lead to excessive microglia activation and contribute to the behavioral changes observed in depression in adulthood.
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http://dx.doi.org/10.3389/fncel.2015.00082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357262PMC
March 2015

Prenatal administration of lipopolysaccharide induces sex-dependent changes in glutamic acid decarboxylase and parvalbumin in the adult rat brain.

Neuroscience 2015 Feb 18;287:78-92. Epub 2014 Dec 18.

Laboratory of Pharmacology and Brain Biostructure, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland.

Rationale: Recent clinical studies suggest GABA-ergic system abnormalities as a neuropathological mechanism of schizophrenia.

Objectives: In the present study, we examined the effect of chronic prenatal lipopolysaccharide (LPS) administration on immunohistochemical changes of glutamate decarboxylase (GAD67) and parvalbumin (PV)-expressing neurons in the medial prefrontal cortex and hippocampus of rats.

Results: These data demonstrated that prenatal LPS administration during the final 2 weeks of pregnancy induced schizophrenia-like behavioral symptoms, such as deficits in sensorimotor gating (prepulse inhibition) and impairments in social interactions and exploration, in adult offspring. Moreover, immunohistochemical analysis revealed that in our neurodevelopmental model of schizophrenia, decreases in the total number of PV- and GAD67-positive neurons in the medial prefrontal cortices of adult females prenatally exposed to LPS were observed, whereas these immunochemical changes were primarily detected in the hippocampus of males. Additionally, a decrease in PV-labeled axon terminals of GABA-ergic cells, likely reflecting the perisomatic inhibitory innervation of pyramidal neurons, was observed in the medial prefrontal cortices in both sexes.

Conclusion: This study provided evidence of a key role for the GABA system in neurodevelopment associated with the etiopathogenesis of schizophrenia and showed that the observed changes are sex-dependent. Moreover, this study is the first to present a model of schizophrenia based on prenatal LPS administration, which not only produced behavioral abnormalities but also changed the cytoarchitecture of the GABA inhibitory system.
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http://dx.doi.org/10.1016/j.neuroscience.2014.12.013DOI Listing
February 2015

Elevated brain glucose and glycogen concentrations in an animal model of depression.

Neuroendocrinology 2014 3;100(2-3):178-90. Epub 2014 Oct 3.

Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.

Introduction: Recent data indicate that there is a link between depression and diabetes and that excess glucocorticoids may play an underlying role in the pathogenesis of both of these diseases. The aim of the present study was to determine whether there are any alterations in glucose, glycogen, glucose transporters, insulin, insulin receptors or corticosterone concentrations in the hippocampus and frontal cortex in a prenatal stress rat model of depression.

Methods: Male rats whose mothers had been subjected to stress and control animals were subjected to the Porsolt test to verify the experimental model. Next, some of the rats were subjected to acute stress and/or were administered glucose. Glucose, glycogen, corticosterone, insulin, insulin receptor, phospho-insulin receptor and glucose transporter (GLUT1, GLUT3 and GLUT4) concentrations were assayed.

Results: Prenatally stressed rats exhibited glucose and glycogen concentrations in both investigated brain structures that exceeded those of the control animals. Prenatal stress also increased the levels of glucose transporters - GLUT1 in both tissues and GLUT4 in the frontal cortex. The changes in the prenatally stressed rats were more prominent in the animals that were subjected to stress or glucose loading in adulthood.

Conclusion: The increase in carbohydrate brain concentrations evoked by prenatal stress may result from changes in the amounts of glucose transporters, especially GLUT1. Moreover, the obtained results support the hypothesis that stress during the perinatal period permanently increases the sensitivity of brain tissue to factors that act in adulthood. © 2014 S. Karger AG, Basel.
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http://dx.doi.org/10.1159/000368607DOI Listing
October 2015